The overarching goal of this program project grant (PPG) continues to be the development of novel[unreadable] therapies for type 2 diabetes. The program has evolved from its genesis in 1999 as a collaboration[unreadable] between three research Centers within the University of Texas Southwestern Medical Center in Dallas[unreadable] (UTSWMC) to its current format, involving collaboration of four Centers located at UTSWMC and Duke[unreadable] University Medical Center. The program will continue with its unique format of melding projects on[unreadable] diabetes mechanisms with projects focused on development of new technologies for studying and[unreadable] treating the disease. In the past funding cycle, the most compelling advances have occurred in the[unreadable] area of pancreatic islet biology and related technologies. We have therefore chosen to focus the[unreadable] competitive renewal of this application on development of new strategies for understanding and[unreadable] reversing beta-cell dysfunction of type 2 diabetes. Project 1 (Newgard) will investigate novel pathways for[unreadable] control of beta-cell function and growth that have emerged in the prior funding period, particularly the role[unreadable] of the homeodomain transcription factor Nkx6.1 in the biology of normal and dysfunctional mature islet[unreadable] cells. Project 2 (Sherry) seeks to develop novel PET and MR agents for molecular imaging of islet[unreadable] beta-cells in vivo. Project 3 (Kodadek) will create cell permeable synthetic molecules capable of[unreadable] activating the expression of specific performance- or growth-enhancing genes in islet beta-cells. These[unreadable] projects will be supported by an Administrative Core (Core A), an Islet Targeting Core (Core B), which[unreadable] deploys two novel technologies for delivery of molecular cargo to islet beta-cells in living animals, and a[unreadable] Metabolomics Core (Core C), which provides state-of-the-art mass spectrometry (MS)- and nuclear[unreadable] magnetic resonance (NMR)-based technologies for comprehensive metabolic profiling and[unreadable] measurement of metabolic flux.